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Trends in Cancer Research   Volumes    Volume 2 
Hereditary Non-Polyposis Colorectal Cancer (HNPCC); definition and diagnostics in 2006
Annika Lindblom, Sam Ghazi, Tao Liu, Kristina Lagerstedt, Nikos Papadogiannakis
Pages: 21 - 31
Number of pages: 11
Trends in Cancer Research
Volume 2 

Copyright © 2006 Research Trends. All rights reserved

Several well-known high-risk colorectal cancer syndromes exist and some predisposing genes are known. In these families genetic counseling and pre-symptomatic testing are motivated and subjects at risk should be offered surveillance programs. The most well known syndromes are Familial Adenomatous Polyposis and Hereditary Non-Polyposis Colorectal Cancer (HNPCC), but there are at least as many families with a family history of autosomal dominantly inherited increased risk of CRC which are not classified as any known syndrome and where surveillance is motivated. HNPCC, also called Lynch syndrome is characterized by an autosomal dominant inheritance of early onset of colorectal cancer and an increased risk of other cancer types in addition to colorectal cancer. HNPCC is caused by germline mutations in DNA mismatch-repair genes (MMR). The incidence of this syndrome has been estimated 1-3%. At least seven MMR genes have been suggested to cause HNPCC. Some genes are estimated to be involved in, at most, a very limited number of families since almost all HNPCC families have been shown to segregate germline mutations in hMLH1, hMSH2 or more rarely hMSH6. It is imperative to verify all true HNPCC families since counseling and genetic testing gives the opportunity to reduce the number of at-risk subjects undergoing surveillance program. Various clinical criteria have been defined in an attempt to pre-select patients/families for a full HNPCC molecular genetic investigation. First, the ICG-HNPCC group defined the Amsterdam criteria, which focused on close relatives with colorectal cancer and an early age of onset. These criteria were later modified to also consider extra-colonic tumors. The frequent finding of microsatellite instability in HNPCC colorectal cancer prompted the use of MSI-testing as a pre-screening method for HNPCC. The “Bethesda guidelines” were developed to assist in the selection of tumors for MSI analysis, and have also been revised at a new NCI workshop in Bethesda. To test for MSI in selected patients appears to be a cost-effective way to identify subjects, other than those fulfilling the Amsterdam criteria, who might benefit from genetic investigation. The feasibility of using immunohistochemistry to detect MSI colorectal cancers has been confirmed. The method shows both high sensitivity and specificity. However, there is a risk of missing a small fraction of MSI positive tumors if only immunohistochemistry is performed since some missense and truncating mutations may be missed. The advantage of immunohistochemistry is rather that it can pinpoint the mutated gene. Efforts have been made in finding rapid and efficient screening methods. Mutation screening using exon by exon PCR based methods for screening typically reveal mutations in 40-60% of Amsterdam families while mutations in families not fulfilling these criteria are much less frequently found. Using a combination with other mutation detection methods aiming to detect also larger genomic rearrangements screening results show much higher mutation rates. In cases where no mutation is found in spite of a positive family history and MSI positive tumor a mutation in the oncogene BRAF could be used to rule out HNPCC as diagnosis in this particular case.
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